Nicotinic acid and nicotinamide, collectively niacins, are the vitamin forms of nicotinamide adenine dinucleotide (NAD+). Eukaryotes can synthesize NAD+ de novo via the kynurenine pathway from tryptophan (Krehl, et al. (1945) Science 101:489-490; Schutz and Feigelson (1972) J. Biol. Chem. 247:5327-5332) and niacin supplementation prevents the pellagra that can occur in populations with a tryptophan-poor diet. It is well-established that nicotinic acid is phosphoribosylated to nicotinic acid mononucleotide (NaMN), which is then adenylylated to form nicotinic acid adenine dinucleotide (NaAD), which in turn is amidated to form NAD+ (Preiss and Handler (1958) J. Biol. Chem. 233:488-492; Preiss and Handler (1958b) J. Biol. Chem. 233:493-50).
NAD+ was initially characterized as a co-enzyme for oxidoreductases. Though conversions between NAD+, NADH, NADP and NADPH would not be accompanied by a loss of total co-enzyme, it was discovered that NAD+ is also turned over in cells for unknown purposes (Maayan (1964) Nature 204:1169-1170). Sirtuin enzymes such as Sir2 of S. cerevisiae and its homologs deacetylate lysine residues with consumption of an equivalent of NAD+ and this activity is required for Sir2 function as a transcriptional silencer (Imai, et al. (2000) Cold Spring Harb. Symp. Quant. Biol. 65:297-302). NAD+-dependent deacetylation reactions are required not only for alterations in gene expression but also for repression of ribosomal DNA recombination and extension of lifespan in response to calorie restriction (Lin, et al. (2000) Science 289:2126-2128; Lin, et al. (2002) Nature 418:344-348). NAD+ is consumed by Sir2 to produce a mixture of 2′- and 3′ O-acetylated ADP-ribose plus nicotinamide and the deacetylated polypeptide (Sauve, et al. (2001) Biochemistry 40:15456-15463). Additional enzymes, including poly(ADPribose) polymerases and cADPribose synthases are also NAD+-dependent and produce nicotinamide and ADPribosyl products (Ziegler (2000) Eur. J. Biochem. 267:1550-1564; Burkle (2001) Bioessays 23:795-806).
The non-coenzymatic properties of NAD+ has renewed interest in NAD+ biosynthesis. Four recent publications have suggested what is considered to be all of the gene products and pathways to NAD+ in S. cerevisiae (Panozzo, et al. (2002) FEBS Lett. 517:97-102; Sandmeier, et al. (2002) Genetics 160:877-889; Bitterman, et al. (2002) J. Biol. Chem. 277:45099-45107; Anderson, et al. (2003) Nature 423:181-185) depicting convergence of the flux to NAD+ from de novo synthesis, nicotinic acid import, and nicotinamide salvage at NaMN (Scheme 1).
